rs781126604
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_021098.3(CACNA1H):c.4720G>C(p.Glu1574Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,611,168 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
CACNA1H
NM_021098.3 missense
NM_021098.3 missense
Scores
2
13
3
Clinical Significance
Conservation
PhyloP100: 9.57
Genes affected
CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000514 (75/1458814) while in subpopulation EAS AF= 0.00189 (75/39688). AF 95% confidence interval is 0.00155. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAdExome at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1H | NM_021098.3 | c.4720G>C | p.Glu1574Gln | missense_variant | 25/35 | ENST00000348261.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1H | ENST00000348261.11 | c.4720G>C | p.Glu1574Gln | missense_variant | 25/35 | 1 | NM_021098.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152236Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000364 AC: 9AN: 246916Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134390
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GnomAD4 exome AF: 0.0000514 AC: 75AN: 1458814Hom.: 0 Cov.: 35 AF XY: 0.0000510 AC XY: 37AN XY: 725794
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74496
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 19, 2018 | This sequence change replaces glutamic acid with glutamine at codon 1574 of the CACNA1H protein (p.Glu1574Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs781126604, ExAC 0.06%). This variant has not been reported in the literature in individuals with CACNA1H-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;.
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D
Sift4G
Uncertain
D;.;D;D
Polyphen
D;.;P;P
Vest4
MutPred
Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at